All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.
G protein-coupled receptors are prevalent throughout the human body, comprising approximately 60% of known cellular receptor types, and mediate signal transduction across the cell membrane for a very wide range of endogenous ligands. They participate in a diverse array of physiological and pathophysiological processes, including, but not limited to, those associated with cardiovascular, central and peripheral nervous system, reproductive, metabolic, digestive, immunological, inflammatory, and growth disorders, as well as other cell-regulatory and proliferative disorders. Agents which selectively modulate functions of G protein-coupled receptors have important therapeutic applications. These receptors are becoming increasingly recognised as important drug targets, due to their crucial roles in signal transduction (G protein-coupled Receptors, IBC Biomedical Library Series, 1996).
One of the most intensively studied G protein-coupled receptors is the receptor for C5a. C5a is one of the most potent chemotactic agents known, and recruits neutrophils and macrophages to sites of injury, alters their morphology; induces degranulation; increases calcium mobilisation, vascular permeability (oedema) and neutrophil adhesiveness; contracts smooth muscle; stimulates release of inflammatory mediators, including histamine, TNF-α, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes, and of lysosomal enzymes; promotes formation of oxygen radicals; and enhances antibody production (Gerard and Gerard, 1994). α
Agents which limit the pro-inflammatory actions of C5a have potential for inhibiting chronic inflammation, and its accompanying pain and tissue damage. For these reasons, molecules which prevent C5a from binding to its receptors are useful for treating chronic inflammatory disorders driven by complement activation.
In our previous application No. PCT/AU98/00490, we described the three-dimensional structure of some analogues of the C-terminus of human C5a, and used this information to design novel compounds which bind to the human C5a receptor (C5aR), behaving as either agonists or antagonists of C5a. It had previously been thought that a putative antagonist might require both a C-terminal arginine and a C-terminal carboxylate for receptor binding and antagonist activity (Konteatis et al, 1994). In PCT/AU98/00490 we showed that in fact a terminal carboxylate group is not generally required either for high affinity binding to C5aR or for antagonist activity. Instead we found that a hitherto unrecognised structural feature, a turn conformation, was the key recognition feature for high affinity binding to the human C5a receptor on neutrophils. As described in our international patent application No. PCT/AU02/01427, filed on 17th October 2002, we used further refinements of these findings to design more tightly constrained structural templates which enable hydrophobic groups to be assembled into a hydrophobic array for interaction with a C5a receptor. We have subsequently found that a preferred compound of this class is able to inhibit cardiac and pulmonary fibrosis, and this is described in our international patent application No. PCT/AU03/00415, filed on 7 Apr. 2003. The entire disclosures of these specifications are incorporated herein by this reference.
Osteoarthritis is a non-inflammatory, chronic degenerative joint condition, characterized by degeneration of articular cartilage; in advanced cases there is also hypertrophy of bone at the joint margins, and changes in the synovial membrane. Secondary changes in underlying bone cause pain and affect joint function.
Osteoarthritis is strongly age-related, with over 50% of people over the age of 70 being treated for this condition. It is also associated with obesity and with over-use injuries, and is common in former athletes who engaged in weight-bearing sports. It is currently estimated that in the United States 35 million people—13 percent of the population—are 65 and older, and that more than half of these people have radiological evidence of osteoarthritis in at least one joint. By 2030, 20 percent of Americans—about 70 million people—will have passed their 65th birthday and will be at risk for osteoarthritis. It is estimated that there are about 103 million osteoarthritis sufferers in the European Union.
At present, therapies available to treat osteoarthritis are limited to the use of analgesics or anti-inflammatory agents, reduction in pressure across the joint, and weight loss. Most current treatments are designed only to relieve pain and/or inflammation, and to reduce or prevent the disability caused by bone and cartilage degeneration. COX-II inhibitors such as Celebrex, Vioxx and Bextra, which target inflammation, have recently become available for the treatment of this condition. To our knowledge none of these approved or experimental agents, and in particular no small molecule agent, targets the C5a receptor.
The available drug therapies target the symptoms but not the underlying cause of this disease; none of them inhibits the degenerative structural changes which are responsible for its progression. The disease continues to progress, and total joint replacement, especially of the hip or knee, is ultimately necessary in many patients. Furthermore, clinical testing of new therapies is complicated by the fact that the disease manifests itself differently in each person.
A variety of agents, ranging from tumour necrosis factor antagonists to dietary supplements such as S-adenosyl methionine or boron compounds, are in various stages of clinical trial. However, there is a great need in the art for effective, non-toxic agents which do not require administration by injection, and which can be produced at reasonable cost.